CD8 T cells play an important role in the clearance of many viral infections and in providing protective immunity against re-infection. In assessing the effectiveness of the CD8 T cell response, most studies have focused on correlating the magnitudes of the response with the level of protection it provides. However, recent studies have shown that effective control of viral infection is dependent on not only the quantity but also the quality of antigen-specific CD8 T cells. Using infection of mice with lymphocytic choriomeningitis virus (LCMV) as a model, we have discovered that memory CD8 T cells generated in the absence of CD4 T cell help are of poor quality. These "unhelped" memory CD8 T cells have a decreased ability to persist, produce low levels of effector cytokines following restimulation, and most significantly, do not provide adequate protection against secondary challenge. This loss of functionality in CD8 T cells is also observed during chronic LCMV infection and is thought to contribute to the failure of the host to clear the infection. Our recent studies have been focused on elucidating the mechanisms behind why "unhelped" CD8 T cells are unable to function properly. We have shown that defects in "unhelped" memory CD8 T cells are not due to aberrations in the TCR repertoire nor to impairment in functional avidity maturation. Instead, our results show that the defect lies downstream of TCR signaling and is due to a failure of these cells to undergo specific epigenetic modifications at several loci critical for effector functions. We will test the hypothesis that a failure of CD8 T cells to undergo requisite epigenetic modifications contributes to their inability to function properly during chronic LCMV infection. More specifically, in Aim 1 we will determine if differences in epigenetic remodeling contribute to the inability of antigen-specific CD8 T cells to function properly during chronic infection. In Aim 2, we will examine if the defective CD8 T cells that arise during chronic infection can be reprogrammed through epigenetic modification to gain full functionality. The results of these studies may help us develop new strategies that will improve the functionality of CD8 T cells and thus enhance immune control of viral infection. PUBLIC HEALTH RELEVANCE Clearance of many viral infections is critically dependent on the function of CD8 T cells. Recent results have shown that CD8 T cells become functionally defective when CD4 T cell help is absent. This loss of functionality in CD8 T cells is also observed during chronic viral infection and is thought to contribute to the failure of the host to clear the infection. In this study, we aim to understand why CD8 T cells become defective during chronic viral infection and in the absence of CD4 T cells help. In doing so, we hope to develop new strategies that will enhance the functionality of CD8 T cells and thus immune control of viral infection.